Imran et al.

Nutrition Journal (2015) 14:71

DOI 10.1186/s12937-015-0059-3

REVIEW Open Access

Potential protective properties of flax

lignan secoisolariciresinol diglucoside
Muhammad Imran1*, Nazir Ahmad1, Faqir Muhammad Anjum1, Muhammad Kamran Khan1, Zarina Mushtaq1,
Muhammad Nadeem2 and Shahzad Hussain3

Abstract
Lignans are a group of phytonutrients which are widely distributed in the plant kingdom. Flaxseed is the richest
source of providing lignan precursor such as secoisolariciresinol diglucoside (SDG). This article reviews the studies
relevant to experimental models in animals and humans demonstrating the possible nutraceutical actions of SDG
to prevent and alleviate lifestyle-related diseases. A local and international web-based literature review for this
project was carried out to provide information relating to the study. The major key word “SDG” was selected to
gather information using the electronic databases pertaining to the current state of flaxseed lignans composition,
bioactive compounds, metabolism and to find out their role in terms of chemopreventive action. The extraction
methods vary from simple to complex depending on separation, fractionation, identification and detection of the
analytes. The majority of studies demonstrate that SDG interferes with the development of different types of
diseases like cardiovascular, diabetic, lupus nephritis, bone, kidney, menopause, reproduction, mental stress,
immunity, atherosclerosis, hemopoietic, liver necrosis and urinary disorders due to its various biological properties
including anti-inflammatory, antioxidant, antimutagenic, antimicrobial, antiobesity, antihypolipidemic and
neuroprotective effects. Moreover, SDG has a defending mediator against various cancers by modulating multiple
cell signaling pathways. As discussed in this review, SDG has shown therapeutic potential against a number of
human diseases and can be recommended for discerning consumers.
Keywords: Flaxseed, Processing, Lignan, Precursors, Diet, Therapy, Maladies

Background biologically active components such as dietary fiber

The flaxseed (Linum usitatissimum L.) is the seed from
the flax plant, an annual herb which belongs to Linaceae
family with more than 200 species. The Latin name of
flaxseed means “very useful”, and it has brown and
golden varieties. The shape of flaxseed is flat or oval up
to 4–6 mm size with a pointed tip. Flaxseed has been a
part of human diet for thousands of years in Asia, Europe,
Africa, North America and more recently in Australia.
The world flaxseed production remained static about
2.6 million tonnes as compared with other oilseed crops
and represents 1 % of total world oilseeds supply. Cur-
rently, flaxseed has been the focus of increased interest
in the field of diet and disease research due to the po-
tential health benefits associated with some of its
* Correspondence: imran@gcuf.edu.pk
1
Institute of Home and Food Sciences, Faculty of Science and Technology,
Government College University, Faisalabad 38000, Pakistan
Full list of author information is available at the end of the article
(25–28 %) and α-linolenic acid (50–55 % of total fatty
acids composition) [1].
Among the compounds that present biological activity,
phenolic compounds are of special interest. Lignans,
very complex classes of bioactive polyphenolic phyto-
chemicals, formed by the coupling of two coniferyl alco-
hol residues are widely distributed in the plant kingdom
[2]. There are two general types of lignans: i) those
found in plant seeds like secoisolariciresinol diglucoside
(SDG), isolariciresinol, matairesinol, lariciresinol and ii)
those found in animals and humans known as mamma-
lian lignans [3]. Phenolic lignans are found in most
fiber-rich plants, including pumpkin seed, sesame seed,
grains such as wheat, barley, rye and oats; legumes such as
beans, lentils, and soybeans; and vegetables such as garlic,
asparagus, broccoli, and carrots. Flaxseed is particularly
the richest known source of lignans (9–30 mg per g), with
lignan production at 75–800 times that of other oil seeds,

© 2015 Imran et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
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Imran et al. Nutrition Journal (2015) 14:71
cereals, legumes, and fruit and vegetables [4]. The princi-
pal dietary lignan present in flaxseed is SDG which occurs
as a component of a linear ester-linked complex. Chem-
ically, the C6-OH of the glucose of SDG is esterified to the
carboxylic acid of hydroxymethylglutaric acid. Accumula-
tion of SDG is coherent with LuPLR gene expression and
synthesis of PLR enzyme during mature seed development
[5]. The understanding of the action mechanism of these
SDG compounds is crucial for their possible exploitation
as neutraceutical supplement in biological system.
Methods for literature search
The search for relevant literature was conducted using
electronic databases which were searched for peer-
reviewed journal articles and further expanded our
search to latest available books of food and nutrition by
visiting websites and by consulting with reference librar-
ians and experts in the field. Specifically, various words
such as ‘Flaxseed’, ‘Processing’, ‘Lignan’, ‘Precursors’, ‘Diet’,
‘Therapy’, ‘Maladies’ were searched in keyword, title, or
abstract of an article or related books. Particular data-
bases used were: ‘American Society of Agriculture and
Biological Engineers (ASABE)’, ‘SAGE online journals’,
‘Nature Publishing’, ‘Cambridge University Press’, ‘Elsevier
(Science Direct)’, ‘Jastor’, ‘Science Online’, ‘Springerlink’,
‘Taylor and Francis Journals’, ‘Wiley-Blackwell Journals’,
‘Beech Tree Publishing’, ‘ISI Web of Knowledge’, ‘Agricola’,
‘Agris’, ‘Biomed Central’, ‘Cancer.gov’, ‘Directory of Open
Access Journals’, ‘Google Directory’, ‘High Wire Press’,
‘Pubmed’, ‘SciELO-Scientific Electronic Library Online’,
‘Scopus’ and ‘Health Source’. Reference lists of all rele-
vant articles were examined for additional studies. After
collection of search literature, abstracts and articles were
classified as highly relevant, moderately relevant or ir-
relevant. Highly relevant articles were those in which
direct extraction of SDG and derived mammalian lig-
nans from flaxseed or flaxseed by-products was carried
out. Moderately relevant articles were those that failed
to meet the ‘highly relevant’ criteria yet provided back-
ground information regarding other phenolic com-
pounds of flaxseed. Inclusion criteria were based on
animal and human models with respect to SDG treat-
ment for different maladies. All other articles were
deemed irrelevant to this review and considered as ex-
clusion criteria based on insufficient information was
available to permit methodological evaluation for SDG
extraction, analysis and processing or if complex multi-
modal efficacy programmes were used. Three subject ex-
perts from the institute were invited for independently
applied the inclusion/exclusion criteria to papers identi-
fied from the literature search as highly relevant before
combining results. A consensus method was used to
solve any dispute regarding the inclusion or exclusion of
a study. A fourth reviewer was consulted to resolve
Page 2 of 7
disagreements [6]. On the basis of the criteria specified
above, as of May of 2015, total 220 while 140 moderate
relevant articles were found in electronic database. From
which only 70 highly relevant articles were part of
results.
Extraction, isolation and purification of SDG
Most of the analytical techniques for the extraction,
isolation, and purification of SDG have been conducted
on whole flaxseed and defatted flaxseed meal. Flaxseed
lignans especially SDG occur in ester-linkage form in
the hulls enclosing the seeds, which require special pre-
treatments including various steps and combinations of
enzymatic, acidic, and alkaline hydrolysis before extrac-
tion and analysis [7, 8]. Bakke and Klosterman firstly
reported a laboratory process for extracting SDG from
defatted flaxseed meal using equal parts of 95 % ethanol
and 1,4-dioxane [9]. Furthermore, several scientists
used a variety of organic solvents mixture such as of
methanol, acetone, isopropanol and butanol to extract
SDG [10]. Base hydrolysis treatments include sodium,
calcium, ammonium and potassium hydroxides for the
liberation of SDG from flaxseed lignan polymer [7]. Re-
cent studies have evidenced that the applications of
novel technologies for extraction of SDG compounds
from flaxseed oilcake is of particular interest within the
context of green chemistry as these technologies use re-
duced solvent consumption, reduced extraction time,
lower temperature, less thermal damages to the extract
and minimize the loss of bioactive compounds in com-
parison to other conventional published methods [11].
Considering the importance of the phenolic fraction of
flaxseed, high performance analytical methods have
been developed to characterize its complex lignan poly-
mer pattern. The analytical methods depending upon
separation methodology for SDG can be categorized
into chromatographic and non-chromatographic tech-
niques. In most research studies, gas chromatography,
high-performance liquid chromatography coupled with
photodiode array detector and mass spectrometric pro-
cedures have been used for the quantification and ana-
lysis of SDG purity [12, 13].
SDG-enrich foods
SDG can be successfully supplemented in numerous
foods due to high stability percentage in finish products.
SDG has been found to withstand baking temperatures
(250 °C) and can be incorporated in cereal-based bakery
products [14]. The SDG concentration of doughs, baked
rye breads, graham buns, and muffins was found rela-
tively stable during storage at room temperature for
1 week and at −25 °C for 2 months, respectively [15].
Similarly, macaroni fortified with whole ground flax-
seed at levels of 10 to 20 %, dried under ultrahigh
Imran et al. Nutrition Journal (2015) 14:71
temperature (90 °C) and stored for 32 weeks under am-
bient conditions possessed approximately 80 to 95 % of
the SDG contents [16]. Quantitative recovery of SDG
from the commercially prepared breads was observed
when product formulation was supplemented with pure
SDG. However, 73–75 % recovery of SDG was noted
from baked bread samples which contained flax meal
or aqueous alcohol extracts in product recipe. The ex-
tent of grinding of the flaxseed was also shown to have
a significant effect on the recovery of SDG from both
flax meal breads and baked goods, with extraction of
SDG from finely ground samples greater than that from
course material [17]. A great part of the SDG content
(89 %) was found stable during the heat treatment of
ground flaxseed, either alone or as an ingredient in
bread, under various conditions of temperature and
during storage for several days [18]. Added SDG was
retained in the whey fraction and 6 % was found in the
cheese curd while up to 25 % of added SDG was lost in
whey-based drinks during storage of 6 months at 8 °C
[19]. SDG shows natural antioxidant mechanism in foods
and prevents oxidation reactions resulting in enhanced
shelf life of foods. The ethanolic flaxseed extracts enriched
with SDG compounds exhibit antioxidant activity during
frozen storage of meat products. However, antioxidant ef-
ficiency of the SDG-enriched extracts seems to depend on
chemical composition of raw material and flax variety
[20]. Moreover, thermal processing has been responsible
for slight increase in extractability level of the lignans from
raw flaxseed meal which is may be due to increasing por-
osity of the heated seeds. One recent scientific study re-
ported that the flaxseed samples heated at 250 °C for
3.5 min possessed high SDG contents (1200 mg/100 g)
when compared from unheated flaxseed samples
(1099 mg/100 g) [14]. However, to conserve the relatively
high content of lignans during production of commercial
foods products, the initial raw material composition, the
water content and the applied temperatures have to be
considered.
Bio-activation of SDG
The biological activity of SDG results from their conver-
sion to the mammalian lignans enterolactone (EL) and
enterodiol (ED) by the intestinal microflora in the upper
part of the large bowel. The mammalian lignans differ
from plant lignans in that mammalian lignans have the
hydroxyl groups in the meta position while plant lignans
have the oxygenated substituents primarily in the para
positions [21]. The mammalian lignans, firstly identified
in humans and animals in 1980 [22], are formed in the
human body by the action of diverse phylogenetically bac-
terial strains dominating Peptostreptococcus sp. SDG-1
and Eubacterium sp. SDG-2 present in the gastrointestinal
(GI) tract through hydrolyzing the sugar moiety of plant
Page 3 of 7
lignan precursors followed by dehydroxylation and de-
methylation process [23]. Many factors, in addition to diet,
such as intestinal microflora, smoking, antibiotics, and
obesity affect circulating lignan levels in the body [24].
Due to variations in these factors, large differences among
individuals have been observed in lignan bio-activation in
urine, fecal and blood samples. Different studies have ana-
lyzed human intake of lignans. However, so far research
has not shed light on what proportion of ingested mg of
plant lignans is metabolized in the gut, absorbed and fi-
nally reaches target tissue [23]. Mammalian lignan pro-
duction from intake of whole or milled flaxseed
supplemented baked products is dependent on time and
dose but not on processing. The processed flaxseed sup-
plemented muffin or bread did not affect the quantity of
lignan excretion in womens which reflect stability and
bioavailability of plant and mammalian lignans in human
biological metabolism [25].
Chemopreventive properties of SDG
Flaxseed Lignan precursors and their mammalian me-
tabolites may be appreciated as health promoting dietary
micronutrients having chemopreventive properties in
animals and humans by utilizing as nutraceutical agent
against different chronic diseases like cancer, athero-
sclerosis, diabetes, kidney disorders and lupus nephritis
[26]. Some of the health effects of flax SDG are dis-
cussed in the following sections.
Anti-cancer effect
The animal and human studies have shown the preven-
tion role of SDG against some cancers (breast, lung and
colon) as a result of its strong anti-proliferative, antioxi-
dant, anti-oestrogenic and/or anti-angiogenic activity. It
is proposed that the anticancer activity of SDG is associ-
ated with the inhibition of enzymes involved in carcino-
genesis. The growth of crypts and crypts foci are the
earlier risk factor for colon cancer. The animal studies
have showed that flaxseed SDG and lignan supplementa-
tion in rat’s diet resulted in aberrant crypts and it foci
showing the anticancer role of these molecules [27].
Similar, the anti carcinogenic effect of SDG molecule
has been observed in pulmonary metastasis, mammary
gland and breast cancer metastasis. The studies showed
that the supplementation of SDG in mice diet resulted
in reduction of volume, area and numbers of tumors sig-
nificantly as compared to control mice group. The two
week supplementation of SDG in mice diet led to 22 %
more pulmonary metastasis tumors in melanoma cells
than average tumors as compared to control group hav-
ing 59 % more tumors than average [28]. The SDG of
flaxseed are proven to initiate the differentiation of en-
hancement of terminal end buds in mammary gland and
thus have role in prevention of breast cancer. The series
Imran et al. Nutrition Journal (2015) 14:71
of studies have shown that progression of N-methyl-N-
nitrosourea-induced mammary tumorigenesis results in
development of carcinogenesis and SDG has proven to
delay the progression of this phenomenon by regulating
the terminal end bud differentiation [29, 30]. There are
several possibilities that how SDG can biologically involve
in delay or prevention of carcinogenic phenomenon. It is
supposed that plasma insulin-like growth factor I, endo-
thelial growth factor is responsible for risk factor of breast
cancer progression and SDG can lower these growth fac-
tors [31, 32]. Another possibility of prevention role of
SDG is in mediation of Zn concentration which observed
more in breast cancer tissue compared to tissue of normal
breast which may provide protection against breast cancer
by limiting angiogenesis in such cases [33].
Human studied have shown that there could be con-
sisted possibility of correlation between SDG and can-
cer. SDG may affect hormonal levels and may influence
cancer progression. The potential effects of SDG are
attributed to concomitant fat restriction. The research
studies conducted by Demark-Wahnefried and co-
workers [34, 35] on prostate cancer proliferation in hu-
man subjects have shown that flaxseed-supplemented
could affect the biomarkers of prostatic neoplasia. A
randomized controlled trial test on 161 prostate cancer
patients for 30 days before prostatectomy were con-
ducted by assigning diet without flaxseed supplementa-
tion and flaxseed-supplemented of 30 g/day. The
proliferation (Ki-67, the primary endpoint) and apop-
tosis were assessed for tumor development. Prolifera-
tion rates were significantly lowers among men
assigned to the flaxseed supplemented diets. Their find-
ings suggest that flaxseed is associated with biological
alterations that may have prevention role against pros-
tate cancer. The studies from two research groups of
Boccardo et al. [36] and Pietinen et al. [37] have dem-
onstrated a strong correlation between SDG metabo-
lites and breast cancer in women. The serum level of
intestinal microbial derived SDG metabolites enterodial
and enterolactone have inversed association with breast
cancer when studies were conducted on 508 breast can-
cer women cases. The overall animal and human stud-
ies have been suggested SDG and its metabolites may
provide prevention against cancer as result of its anti-
oxidant activity or ability to inhibit enzyme action
involved in steroid hormone metabolism.
SDG and heart diseases
The major hearts diseases are stock, coronary artery dis-
ease, peripheral artery disease which are resulted from
oxidative stress, inflammation, obesity, diabetes, dyslip-
idemia and hypertension and contribute to an athero-
genic environment that promotes the development of
myocardial infarction and stroke, leading causes of
Page 4 of 7
mortality among industrialized nations [38, 39]. The ani-
mal and human studies have suggested that SDG and its
metabolites mediate the serum total cholesterol, low dens-
ity lipoprotein, total cholesterol and high density lipopro-
tein ratio which lead to less androgenic complication and
antioxidative prevention [40]. A series of research studies
indicates that regular flaxseed with α-linolenic acid and
flax lignan polymer (containing 34–38 % SDG, 10–11 %
3-hydroxy-3-methylglutaric acid and 15–21 % cinnamic
acids) as potential bioactive components or purified SDG
in equimolar concentration have similar antiatherogenic
effects [41].
Similarly, the human studies showed the SDG as poten-
tial cardiovascular protector by mediating the mechanisms
of total cholesterol, LDL-cholesterol, HDL-cholesterol,
triacylglycerides and glucose metabolism. It was ob-
served that 20 hypercholesterolaemia and hypertrigly-
ceridaemia subjects receiving 600 mg SDG per day for
8 weeks led to significant reductions in total choles-
terol, LDL-cholesterol and glucose concentrations com-
pared with the placebo group [42]. Several other studies
have shown that SDG anti-cardiovascular effects are as-
sociated with enterolactone mediating increased expres-
sion of vascular endothelial growth factor, endothelial NO
synthase and haeme oxygenase-1 mediated myocar-
dial angiogenesis. Overall, the majority of studies that
used purified SDG found improvements in markers of
CVD [43].
Anti-diabetic action of SDG
Diabetes is a metabolic syndrome and is characterized
by increases in central adiposity, serum tirglycerides,
serum glucose, blood pressure, inflammation and de-
creases in HDL-cholesterol that elevates risk of insulin
resistance [44]. The animal and human studies revealed
that high fat diet containing 0 · 5 to 1 · 0 % SDG reduces
liver triglycerides content, serum triglycerides, total
cholesterol, and insulin and leptin concentrations that
resulted in significantly reduced visceral fat gain as com-
pared to group of mice receiving high fat diet without
SDG [45]. Another study have shown that female rats
receiving glucosuria induced diet with SDG have 80 %
less chances of glucosuria as compared to rats have
100 % chances of glucosuria receiving diet without SDG
[46]. SDG reduces C-reactive protein concentrations
which are associated with insulin resistance and diabetes
mellitus in type 2 diabetics [47]. Daily consumption of
low-fat muffin enriched with SDG (500 mg/day) for
6 week can reduce CRP concentrations [48]. The earlier
studies indicate that flaxseed lignan supplements have
beneficial associations with C-reactive protein and also
suggest that lignans have possible lipid- and blood
pressure-lowering associations [49].
Imran et al. Nutrition Journal (2015) 14:71
SDG effect on liver necrosis
The free radicals and reactive oxygen species (ROS) are
produced as a result of exogenous chemicals and/or to
the endogenous metabolic processes involving redox
enzymes and bioenergetic electron transfer in the
biological system. These free radicals and ROS thus in-
duce oxidative stress leading to damage of proteins,
lipids and nucleic acid and results in cancer, diabetes,
atherosclerosis, hepatic diseases. The actions of these
molecules can be nullified through antioxidants mech-
anism [50, 51]. Antioxidant potential of SDG and its
metabolites have been reported in several animal and
human models. Animal studies have shown that SDG
containing flaxseed extract significantly increases the
levels of serum ALP, ALT, AST, Bilirubin, blood urea
and creatinine with decrease in the levels of total pro-
tein and albumin in experimental rabbits exposed with
induced hepatotocxicity compared to the control group.
The SDG polymer complex can significantly prevent
liver and renal damage from paracetamol induced hepa-
tonephrotoxicity in rabbits. Thus, the flaxseed lignan
act as a therapeutically useful hepato-nephroprotective
agent [52]. Flaxseed supplementation may provide a
new therapeutic strategy to reduce hypertriglyceridemia
and fatty liver in rats [53]. Another study reported the
rabbits exposure to SDG lignans for consecutive
8 weeks to assess histopathologic evaluation score of
non-alcoholic fatty liver disease and suggested that
SDG (8 mg/kg) can protective from liver diseases [54].
Intervention studies have shown that Flaxseed lignan
can decreases liver disease risk factors in moderately
hypercholesterolemia mens. The oral administration of
SDG would decrease the level of blood cholesterol and
liver disease risk factors induced by hypercholesterol-
emia in humans. Thirty men received placebo and cap-
sules of SDG for 12 weeks and subjects received 100 mg
of SDG exhibited a significant reduction in the ratio of
low-density lipoprotein/high-density lipoprotein choles-
terol, a significant percentage decrease in the levels of
glutamic pyruvic transaminase and γ–glutamyl transpep-
tidase and a significant percentage decrease in the level
of γ–glutamyl transpeptidase which may reduce the hep-
atic diseases risks [55].
SDG effect on lupus nephritis, bone strength and kidney
disease
Faxseed SDG has a therapeutic role in animal and hu-
man lupus nephritis. SDG significant delays the onset of
proteinuria with preservation in GFR and renal size in a
dose-dependent fashion [56]. Purified SDG during early
life of a young rat animal sensitize bone strength due to
low endogenous levels of sex hormones but having no
negative effects on bone strength and bone health, as
measures of bone mass in adulthood [57, 58]. SDG in
Page 5 of 7
addition with low-dose estrogen therapy, provides the
greatest protection against ovariectomy-induced bone
loss [59]. However, SDG shows no effect on bone min-
eral density content, body composition, lipoproteins,
glucose level and inflammation [44]. SDG have a benefi-
cial role in chronic renal disease like reduces weight,
renal inflammation and lipid peroxides in polycystic kid-
ney disease [60].
Menopause, urinary composition and reproduction effect
The occurrence of menopause is associated with an in-
creased risk of cardiovascular events and this has par-
tially been attributed to the decline in circulating levels
of estrogen. SDG supplementation produces a dose-
related cessation or lengthening (by 18–39 %) of estrous
cycles, reduces immature ovarian relative weight and de-
lays puberty in experimental animals [61, 62]. The daily
consumption of a low-fat muffin enriched with SDG
(500 mg/day) for 6 week had no effect on endothelial
functioning in healthy postmenopausal women [63].
Dietary flaxseed SDG (600 mg/day) can appreciably im-
prove lower urinary tract symptoms in benign prostatic
hyperplasia subjects [64]. Urinary composition or blood
levels of radioactive lignans were not affected by the
duration of SDG exposure while chronic SDG exposure
alters lignan disposition in rats, however; it does not
change the metabolite profile [65]. There were no sig-
nificant effects of exposing male or female offspring to
SDG during suckling on any measured reproductive in-
dices [66]. SDG affects the reproductive development of
offspring with caution when consuming flaxseed during
pregnancy and lactation [67].
Mental stress and immunity effect
Flax lignan SDG may be associated with the least increase
in peripheral resistance as result the greatest reduction in
plasma cortisol and the smallest increase in plasma fi-
brinogen measured during mental stress [68, 69]. SDG has
long acting hypotensive effect mediated through the gua-
nylate cyclase enzyme. SDG supplementation shows no
significant effects on lymphocyte proliferation indicating
that SDG has no side effects on the immune system [70].
Conclusions
The clinical and laboratory evidences indicate that flax-
seed lignans particularly SDG have numerous biological
properties that make them unique and very useful in
promoting health and combating various diseases. Fu-
ture biological and interventional studies need the con-
firmation of SDG as safe and effective for the prevention
of lipid, protein and DNA oxidation associated with oxi-
dative stress. The potential health benefits of SDG with
supporting evidences from human and animal studies
offers suggestions for future research.
Imran et al. Nutrition Journal (2015) 14:71
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MI, NA, MKK, ZM, MN and SH collected data for this review work and helped
for drafting the manuscript. FMA provided the technical assistance and
guided in the data collection. “It’s also confirmed that all the authors read
and approved the final manuscript”.
Acknowledgement
Authors thanks the Library Department, Government College University
Faisalabad (GCUF) and IT Department, Higher Education Commission (HEC)
for access to journals, books and valuable database.
Author details
1
Institute of Home and Food Sciences, Faculty of Science and Technology,
Government College University, Faisalabad 38000, Pakistan. 2Department of
Dairy Technology, University of Veterinary and Animal Sciences, Lahore,
Pakistan. 3Department of Food Science and Nutrition, College of Food and
Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia.
Received: 6 February 2015 Accepted: 14 July 2015
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